Marc Lalande

Lab Discovery Could Lead to Prader-Willi Treatment

DNA strand


Stem cell researchers at UConn Health have reversed Prader-Willi syndrome in brain cells growing in the lab, findings they recently published in Human Molecular Genetics.

The discovery provides clues that could lead to a treatment for Prader-Willi, a genetic disorder that occurs in about one out of every 15,000 births, and is the most common genetic cause of life-threatening childhood obesity.

Unlike many genetic syndromes that are caused by a mutation in a gene, people with Prader-Willi often have the right gene available — it’s simply that it’s been silenced.

The gene is silenced because it is on the part of their chromosome they inherited from their mother, and for mysterious reasons our cells use the father’s copy of this gene. But if the father’s copy is missing, the cells can’t express that gene at all.

UConn Health’s Maeva Langouet, a post-doctoral fellow; Marc Lalande, professor emeritus of genetics and genome sciences; and their colleagues wondered if it was possible to reverse the silencing of the mother’s copy.

Unlike many genetic syndromes that are caused by a mutation in a gene, people with Prader-Willi often have the right gene available — it’s simply that it’s been silenced.

The researchers noticed that a certain protein, called ZNF274, was involved in the process. It silences many other genes as well, but in those cases it usually acts with another protein. On the Prader-Willi region of our DNA, the protein seems to act alone, they said.

So Langouet and Lalande took stem cells donated by Prader-Willi patients and carefully deleted ZNF274. They then encouraged the stem cells to grow into neurons, a type of brain cell. And the cells seemed normal. They grew and developed, as expected.

Critically, the new cells also expressed the maternal copy of the Prader-Willi region.

“We still need to figure out if knocking out ZNF274 is doing anything else” that might be undesirable, says Langouet.

And many other questions still need to be answered: Does this work directly in human brain cells? Will it only work in embryos, or can it help the brain develop normally even after birth?

Currently, there is no cure for Prader-Willi syndrome, and most research has been targeted towards treating specific symptoms. For many individuals affected by the disorder, the elimination of some of the most difficult aspects of the syndrome, such as the insatiable appetite and obesity, would represent a significant improvement in quality of life and the ability to live independently.

But in the future, this new line of research may offer a therapeutic approach for kids with Prader-Willi, Langouet says.

The research was funded by the Foundation for Prader-Willi Research, the Cascade Fellowship, and the CT Regenerative Medicine Fund.

Lab Notes – Winter 2015

Cancer Cells Unreceptive to Vitamin D

Many human colon cancers may not express receptors for vitamin D, limiting vitamin D’s protective role against colon cancer to the early stages of the disease, report Charles Giardina and colleagues at UConn’s Department of Molecular and Cell Biology and Center for Molecular Medicine in the April 14 issue of Cancer Prevention Research. The researchers observed that adenomas in the colons of mice tended to repress vitamin D receptors, while having elevated Class I histone deacetylases (HDAC). However, HDAC inhibitors may reactivate the vitamin D receptors. They propose that vitamin D could still be protective against colon cancer, but how its receptors are expressed and inhibited in cancer cells needs more examination. Read the article at Cancer Prevention Research.

a group of vitamin D suppliments


Rogue X Chromosomes Uncovered in Farmington

Humans only need the genes from one X chromosome to be healthy. The extra one gets trussed up and shut down in the earliest stages of development. But female human embryonic stem cells growing in the lab sometimes reactivate their second X. They express extra genes, fouling up experiments and scuttling potential therapies. Now, researchers including UConn’s Marc Lalande and a team from Paris Diderot University have found a marker, and potentially a mechanism, for how the extra X reactivates – and they have an idea on how to prevent it. They describe their findings in the May 7 issue of Cell Stem Cell.


Friends are Unreliable Sources for Drinking Studies

In recent years, researchers have turned to friends of people in alcohol studies to verify what the subjects report about their drinking habits. People in the same social situations are sought out, in part, because of the inherent impairment caused by alcohol. But according to a UConn study published in Addictive Behaviors, friends don’t seem to provide any new information. In fact, they typically underreport what their acquaintances consume. The finding supports the so-called “protective effect” of friends described in other research. A growing availability of other evidence – hair and fingernail samples, for example – may provide better strategy for corroborating the amount of alcohol study subjects consume, says author Michael Fendrich, associate dean of the School of Social Work.


She Smells Him, She Smells Him Not

Mice rely on their noses to help them navigate the world. But high levels of progesterone “blind” receptors in the noses of female mice to male pheromones, UConn Health’s John Peluso and other colleagues, led by Dr. Lisa Stowers of The Scripps Research Institute, report in the June 4 issue of Cell. Female mice have high levels of progesterone during the infertile phase of their reproductive cycles, and tend to be indifferent or even aggressive toward males. But during the fertile phase, progesterone levels drop and estrogen rises, and their nasal receptors again respond to male pheromones, the researchers found. Female mice in their fertile phase are friendly and sexually receptive towards males – perhaps because they can smell them.

mouse